B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity

Zhang, Baihao; Vogelzang, Alexis; Miyajima, Michio; Sugiura, Yuki; Wu, Yibo; Chamoto, Kenji; Nakano, Rei; Hatae, Ryusuke; Menzies, Rosemary J.; Sonomura, Kazuhiro; Hojo, Nozomi; Ogawa, Taisaku; Kobayashi, Wakana; Tsutsui, Yumi; Yamamoto, Sachiko; Maruya, Mikako; Narushima, Seiko; Suzuki, Keiichiro; Saito, Hiroshi; Murakami, Kosaku; Hashimoto, Motomu; Ueno, Hideki; Kobayashi, Takashi; Ito, Katsuhiro; Hirano, Toshio; Shiroguchi, Katsuyuki; Matsuda, Fumihiko; Suematsu, Makoto; Honjo, Tasuku; Fagarasan, Sidonia

doi:10.1038/s41586-021-04082-1

Cited by 223 publications

(174 citation statements)

References 56 publications

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“…Excessive production of antibodies by plasma cells can also lead to immune complexes that may modulate the tumor microenvironment (TME) and induce myeloid-derived suppressor cells (2). A recent study provided evidence that B cells can elicit IL-10 + macrophages by synthesizing and secreting the neurotransmitter GABA, which in turn can inhibit the cytotoxic function of CD8 + cells (13). These studies illustrate the complex and heterogeneous roles of B cells within the TME.…”

Section: B Cells and Poor Clinical Outcome In Some Cancersmentioning

confidence: 97%

B cell receptor signaling strength modulates cancer immunity

Ye¹,

Lee²

2022

Journal of Clinical Investigation

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Section: B Cells and Poor Clinical Outcome In Some Cancersmentioning

confidence: 97%

B cell receptor signaling strength modulates cancer immunity

Ye¹,

Lee²

2022

Journal of Clinical Investigation

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“…Interestingly, the existence of GABA in tumor tissues implies that it might participate in inflammatory reactions by anchoring invasive immune cells [50]. Moreover, recent studies show that GABA secreted from B cells provokes a protumor immune environment [51,52]. GABA is mainly derived from gastric cancer cells [53][54][55][56][57] and participates in tumorigenesis via PNI.…”

Section: Epinephrine (E) and Norepinephrine (Ne)mentioning

confidence: 99%

The Nervous System Contributes to the Tumorigenesis and Progression of Human Digestive Tract Cancer

Dai

Liu

2022

Journal of Immunology Research

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Tumors of the gastrointestinal tract are one of the highest incidences of morbidity and mortality in humans. Recently, a growing number of researchers have indicated that nerve fibers and nerve signals participate in tumorigenesis. The current overarching view based on the responses to therapy revealed that tumors are partly promoted by the tumor microenvironment (TME), endogenous oncogenic factors, and complex systemic processes. Homeostasis of the neuroendocrine-immune axis (NEI axis) maintains a healthy in vivo environment in humans, and dysfunction of the axis contributes to various cancers, including the digestive tract. Interestingly, nerves might promote tumor development via multiple mechanisms, including perineural invasion (PNI), central level regulation, NEI axis effect, and neurotransmitter induction. This review focuses on the association between digestive tumors and nerve regulation, including PNI, the NEI axis, stress, and neurotransmitters, as well as on the potential clinical application of neurotherapy, aiming to provide a new perspective on the management of digestive cancers.

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“…Then, we aimed to describe the TME differences between subtypes by using CIBERSORTx derived immune deconvolution and B-cell lymphoma speci c TME gene signatures 19 . CS1 cluster is immunologically "neutral" meanwhile the CS2, which is immunologically depleted, exhibits expression of vascular endothelial cells (VEC), memory resting CD4 + T-cells, monocytes, and activation of GABA synthesis, which has been recently linked to B-cells that inhibit CD8 + T-cells' killer function and promote monocyte differentiation into anti-in ammatory macrophages 20 . The CS4 cluster has a hot-in ammatory TME due to the presence of active CD8 + T-cells and NK cells (with high cytolytic activity score) 21 .…”

Section: Mutational Landscape Of Pcnslmentioning

confidence: 99%

Molecular and clinical diversity in primary central nervous system lymphoma: a LOC Network study

Alentorn

Hernández-Verdin

Kirasic

et al. 2022

Preprint

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Primary central nervous system lymphoma (PCNSL) is a distinct extranodal lymphoma presenting with limited stage disease but variable response rates to treatment despite homogenous pathological presentation. The likely underlying molecular heterogeneity and its clinical impact is poorly understood.We performed a comprehensive genome-wide analysis of 147 PCNSL from fresh-frozen tumor tissue from immunocompetent, treatment naïve PCNSL patients, employing whole-exome sequencing, assessment of somatic copy number alterations and DNA methylation, and RNA expression. These data were integrated and correlated with the clinico-radiological characteristics and outcomes of the patients. We validated our results in an independent series of 93 PCNSL formalin-fixed, paraffin-embedded (FFPE) samples.Consensus clustering of multi-omics data identified four robust, non-overlapping, prognostically significant clusters (CS) within PCNSL. The CS1 group, characterized by high proliferation and Polycomb Repressive Complex 2 (PRC2) complex activity had an intermediate outcome between CS2/CS3 and CS4. Patients who had PCNSL with an “immune-hot” (CS4) profile had the most favorable clinical outcome. In contrast, patients with the immune-cold hypermethylated CS2 and the heterogenous-immune CS3 groups had a poor prognosis. Nearly all PCNSL patients with meningeal infiltration harbored HIST1H1E mutations, enriched in the CS3 group. The integrated analysis suggests that the CS4 group may be more susceptible to immunotherapy. The integration of genome-wide data from multi-omics data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that significantly improved the current clinical stratification. This molecular classification using FFPE samples facilitates routine use in clinical practice and provides potential precision-medicine strategies in PCNSL.

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B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity

Cited by 223 publications

References 56 publications

B cell receptor signaling strength modulates cancer immunity

B cell receptor signaling strength modulates cancer immunity

The Nervous System Contributes to the Tumorigenesis and Progression of Human Digestive Tract Cancer

Molecular and clinical diversity in primary central nervous system lymphoma: a LOC Network study

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